THE IMMUNE SYSTEM

Battle against the microbe world

The Invaders . . .
Bacteria

Viruses
parasites such as fungi, protista, & worms

Nonspecific defenses (innate immunity):

Component of nonspecific defense are present before the onset of infection

Not specific to a particular pathogen but recognizes broad spectra of pathogens

Consist of 3 components: ~ Surface defense : Skin ~ Cellular defense : Phagocytes, macrophages, neutrophils

~ Chemical (protein) defense : lysozymes & complement system

1. Surface defense:
They are effective barriers to the entry of most microbes Eliminate many microbes before they can invade the body tissue It consists of the skin and the mucous membranes lining the digestive, respiratory and urogenital tract.

SKIN-a barrier to infection:

Largest organ (~15% total body weight) Not only acts as a barrier but also uses chemical weapons on the surface Oil and sweat glands makes surface acidic (ph 3-5) Sweat also contains lysozyme, which digest bacterial cell wall It consists of 3 distinct layers: epidermis, dermis and subcutaneous tissue Evoporation

Condt.
Epidermis:10-30 cells:Paper thick Poriasis: replacement 3dvs30d
~ thinner outermost layer -dead cells and keratin(tough & H2O)

-Dermis:
~15-40 time thicker then epidermis

~connective tissue:blood vessel, hair follicle,sweat glands etc.

-wrinkling & leather

Subcutaneous Tissue:var.thick
~contains primarily adipose cells ~acts as a shock absorber and insulator

Other External Surfaces:

Digestive system : Food
~Saliva (which contains lysozymes)

~Acidic environment of the stomach

~Digestive enzymes in the intestine - vomiting & diarhea

Respiratory system : inhaled air

~ mucus

and cilia

~ coughing & swallowing

In urogenital tract
~Acidic urine washes microbes

NONSPECIFIC CELLULAR DEFENCE:2nd LINE OF DEFENCE Surface defenses : Breached

Nonspecific cellular and chemical devices

Responds to any infection Cells : WBC (Leukocytes) ~ Macrophages ~ Neutrophils

~ Natural killer cells (NK Cells)

MACROPHAGES: (big eaters)

~Large,

irregularly shaped cells

~Phagocytosis : engulf viruses, cellulse debris,and dust particles in lungs ~Monocytes : Squeeze through blood capillaries and enters the site of infection (Chemotaxis) ~Differentiated into macrophages (liver, spleen) -Reactive oxygen and nitrogen species formed

-Antigen presenting cells (in specific IR)

-Secrete cytokines (IL-1)

NEUTROPHILS:
~

Most abundant circulating leukocytes

~Like macrophages, they enters the infected tissues ~Where they ingest and kill bacteria by phagocytosis ~In addition, they releases chemicals that kill bacteria in the neighborhood

Electron micrograph of macrophage (pink) attacking e.coli (green)

NATURAL KILLER CELLS:

~Do

Not Attack Invading Microbes Directly

~ They Kill Virus Infected Cell ~Not by Phagocytosis but by Creating Hole in the Membrane of Target Cells ~Perforins,released From the Nk Cells Inserts Into the Membrane of the Target Cells, Forming a Pore ~Immune Surveillance: Against the Cancer Cells

HOW NK CELLS KILL TARGET CELLS

PROTEINS THAT KILL INVADING MICROBES:COMPLEMENT SYSTEM

~20 Proteins

-Antigen Antibody interaction: Bacterial/fungal cell wall

~Membrane Attack Complex formation : A hole in the Cell Membrane In presence of antigen ~ Amplify Inflammatory Response -Chemotaxis: Attract Phagocytes To Infection site,

- Opsonization- Coat The Microbes So That Phagocytes Attach To Them More Readily

HOW COMPLEMENT CREAT A HOLE IN A CELL MEMBRANE

INTERFERONS
~ Acts A Messenger That Protect Normal Cells In The Vicinity Of Infected Cells

~ They Are Of 3 Types: Alpha, Beta And Gamma

~Alpha And Beta Interferons Are Secteted By All Cells :Prevent Viral Replication and protein Assembly ~Gamma Interferon Is Made Only By Particular Lymphocytes And NK Cells -Gamma Interferon Enhances Natural Killer Cell Function And Mactrophage Action -Activity against infected cells and NK cells

THE INFLAMMATORY RESPONSE:

-Localized nonspecific response to infection -Injured cells sec. chemical : histamine and prostaglandins -Vasodilation & reddening - Capillary Permeability : edema (i.e. tissue swelling)

-Chemotaxis : Neutrophil arrives first follwed by macrophages

-Pus: Dead pathogens, cellular debris, tissue cells and Immune response cells

THE EVENTS IN A LOCAL INFLAMMATION

TEMPERATURE RESPONSE: FEVER

2 Fold Action : Microbe & Immune Response Macrophages Releases Interleukin-1 Hypothalamus Temperature Regulation Cells: T & B Cell Proliferation And Activity

Chemical Mediators : Il-1 & Il-2

Stimulate Phagocytosis Liver And Spleen Store Iron (Deplete Microbes) Behavioral Responses : Lizard And Fish HOWEVER HIGH FEVER(> 103of) IS DANGEROUS!!!

Summary of nonspecific host defenses

Vaccines: Edward Jenners experiment

- Smallpox was a common and deadly disease in those days -He observed that milkmaids who had a much milder form of the pox(cowpox) rarely caught smallpox

Condt..
This procedure of injecting a harmless microbe in order to confer resistance to a dangerous one is called Vaccination

Modern attempts to develop resistance to malaria, herpes, and other disease often involve delivering antigen via a harmless vaccinia virus

Condt..
He infected people with cowpox and many of them became immune to small pox We now know that smallpox and cowpox are caused by two different viruses with similar surface antigens Jenners patients injected with the cowpox virus mounted a defense that was also effective against a later infection of the smallpox virus

Louis pasteurs experiment : Active immunity in chickens

-Isolated bacterial culture from chickens with fowl cholera to produced disease if injected to healthy birds

-VACATION/HOLIDAY EFFECT (Left culture on shelf)

-Injected old culture: Birds only slightly ill later on they recovered -Repeated injection with fresh bacteria but still no disease - Reason: Active immunity induced

SPECIFIC /ADAPTIVE/ACQIURED IMMUNITY:

1) Specificity: Distinguish Subtle Differences ~ Eg. Antibodies Can Distinguish A Single Amino Acid.

2) Diversity: Tremendous Diversity In Recognition ~This Help In Recognizing Billions And Billions Of Antigens
3) Memory: Means Second Encounter With The Same Antigen Induces Heightened State Of Immune Response ~ System Can Confer Life-long Immunity To Many Microbes After An Initial Encounter 4) Self/Nonself Recognition: system Distinguish Self From Nonself And Respond To Only Nonself Molecules

SPECIFIC IMMUNITY: SOME TERMS

Antigen: Molecule That Provokes A Specific Immune Response (Foreignness, Size, complexity Chemical nature) ~Usually Present On The Surface Of Microbes
Antigenic Determinants: different Part of a Large Antigen,each Stimulating different Specific Response ~Each Part Serves As A different Antigen ~Receptor Proteins On The Cell Surfaces Recognize An Antigen And Direct Immune Response Antibodies: Proteins Secreted By B-lymphocytes

Humoral Immunity: Antibodies mediated

Cell-mediated Immunity: Immune Response Mediated by T-cells

-Immunoregulation
- Cytotoxicity Active/Acquired Immunity: Generated after exposure(67d). - E.g.Resistance to Chicken Pox Passive Immunity: Transfer of immune component (e.g.Ab) -Transplacental -snake bite

SPECIFIC IMMUNE SYSTEM CELLS

White Blood Cells Or Leukocytes Neutrophils, Eosinophils, Basophils, And Monocytes ~These Cells Are Phagocytes Lymphocytes (T-cells And B-cells)

~Not Phagocytic
~T Cells Directs Cell Mediated Response ~B Cells Direct Humoral Response

B CELLS:
Originate And Mature In Bone Marrow Originally Characterized In A Region Of Chickens Called The Bursa Individual B Cells Recognizes Particular Antigen After Interacting With Antigen It Divide Rapidly Into Plasma cells And Memory B Cells Plasma Cells Acts As A Factory Producing Antibodies Against encountered Antigen Memory B Cells Have A Longer Life Span Than Nave Cells And Express The Same Antibody As Their Parent B Cells

B cells -The Humoral Immune Response:

B cells recognizes invading microbes through receptor protein (antibodies) on their surface Do not attack the microbes but mark them for destruction Marker alert complement proteins, macrophages and NK cells to attack them. Marking is simple and fool proof

Condt..
1. When a B cell encounter an antigen, it enters the B cell by endocytosis and get processed 2. Activated helper T cell recognizes antigen-MHC protein complex on the B cell and releases IL-2 which stimulates B cell to divide

Condt..
3. B cell divides to long-lived Memory cells and short-lived plasma cells (antibody factory) 4. Antibodies are released into the blood plasma which binds to microbes and tag them for destruction..

Structure of Antibodies:
are the proteins in a class called Immunoglobulins (Ig) each antibody molecule consist of 2 identical short polypeptide c/a light chains and two identical long polypeptide c/a heavy chains 4 chains are held together by disulfide (-S-S-) bonds, forming Y-shape molecule

antigen binding specificity resides in the two arms of the Y which has variable amino acid sequence
while the amino acid sequence in the stem of the Y is constant for a given class of immunoglobulins

Structure of an antibody molecule

Structure of an antibody as a B cell receptor.

Classes of Immunoglobulins:
Based on the structure and functions they are of 5 types

IgM
IgG

IgD
IgA IgE Types of light chain -Kappa and Lamda

IgM:
secreted by plasma cells as a homopentamer held together by (-S-S-) bonds.

first type of antibody secreted during the primary response

also promote agglutination activate the complement system first fetal antibody response

IgG:
monomeric in nature major form of antibody in the blood plasma (~80%) predominant antibody secreted during the secondary response activate the complement system also serve as markers that stimulate phagocytosis by macrophages

First antibodies produced in the humoral immune response are IgM This initial wave of antibody production peaks after about one week

Followed by extended production phase of IgG

IgD:
monomeric in nature

serve as receptors for antigen on the B cell surface

assists B-cells in recognizing Ag for which they are specific functions in activation of B-cells subsequent to antigen challenge and differentiation into plasma cells

IgA:
monomer as well as polymers linked by J chain it also contains Secretary component

major form of antibody in body fluids (milk, mucus, saliva)

in milk,they provide immune protection to nursing infants

IgE:
-monomer -binds to mast cell and basophils -associated with degranulation of mast cells and basophils

-promotes release of histamine, inc. vasodilation,capillary permiability,smooth muscle contraction -Chemotaxis:lymphocyte, mac. & complement
-Triggers allergy

Antibody Diversity:
immune system is capable of recognizing millions of antigens

e.g human B cells can make 106 and 109 different antibodies
but chromosome contains only few hundred genes How do the system generate so many different molecules?

Various mechanisms: Somatic DNA rearrangement, Junctional flexibility, and Somatic Hypermutation

Somatic DNA rearrangement:Fig

Junctinal Flexibility:
-Inaccurate DNA joining

-Shifting of reading frame (1/2 base pair addition or deletion) resulting in new sequence
-Increased antibody diversity

Somatic mutation:
-Error in DNA replication during clonal expansion -Increased random mutations -DNA errors specific to lymphocytes

Immunological Tolerance:
mature animals immune system does not respond to that animals own tissue

this is called as Immunological Tolerance

but immune system of embryo responds to both foreign and self molecules and loses the ability to respond to self molecules as its develops

Condt..
two mechanism for immunological tolerance:

~ clonal deletion
~ clonal suppression

During normal maturation of hemopoietic stem cell lymphocytes clones that have receptors for self antigens are either eliminated (clonal deletion) or suppressed (clonal suppression)
Cells learn to identify self antigens because antigens are encountered very frequently

Condt..
If a receptor is activated frequently, it is assumed that the cell is recognizing a self antigen and cells are eliminated or suppressed Some time immunological tolerance fails resulting in autoimmune disease E.g.. In Myasthenia gravis antibodies recognizes acetylcholine receptors on muscle cells, causing paralysis

Active Immunity Through Clonal Selection:

First

time a pathogen invades the body, only few B or T cells recognizes the invaders antigen Binding of the antigen to its receptor on the lymphocyte surface stimulates cell division and produces a clone Clone is a population of genetically identical cells

This process is known as Clonal Selection

In this first encounter, infected person gets sick because there are few cells that can mount immune response and the response is weak This is called a Primary Immune Response

Clonal Selection

Condt:
If the primary response involves B cells, some become plasma cells and other becomes memory cells
Clone of memory cells is specific for that antigen The next time the body is invaded be the same pathogen, a large clone of lymphocytes now exist that recognize that pathogen Due to this the immune response to a second infection is swifter and stronger

This more effective response, elicited by subsequent exposure to an antigen is c/a Secondary Immune Response
Memory cells can survive for several decades!!!!!

Development of active immunity

Antibodies in Medical Diagnosis:

1) Blood Typing:
Class of antigens present on the red blood cells determine blood type of a person

For effective blood transfusion these antigens are very important Several groups of RBC antigens but ABO system is the major group

Condt
~Type A person A antigens on RBC ~Type B person B antigens on RBC ~Type AB person A and B antigens on RBC ~Type O person neither A nor B antigens on RBC

Condt
-Immune system is tolerant to its own RBC antigens -Type A person does not produce anti-A antibodies but have anti-B antibodies

-This is believed due to antibodies made in response to some common bacteria crossreact with the A or B antigen

Condt
-Thus Type A person develop anti-B antibodies by exposure to these bacteria but not develop anti-A antibodies -Type AB persons are tolerance to both antigens thus no antibodies -Type O persons do not develop tolerance and have both anti-A and anti-B antibodies

Agglutination: (Clumping)
Type A blood + serum form type B blood = clumping or agglutination Anti-A antibodies in serum causes type A RBC to clump together

This test allow the blood types to be matched prior to transfusions

Rh Factor:
-Another group of antigens on RBC

-Rh-positive: people who have these antigens

-Rh-negative: do not have these antigens

-Rh-positive allele is more common in humans and is dominant to the Rh-negative allele

Condt..
Its very important in cases where Rh-negative mothers give birth to Rh-positive babies Mothers immune system may get sensitized and produce antibodies against Rh factor

hemolysis of Rh-positive RBC of the fetus

The baby will be anemic (erythroblastosis fetalis or hemolytic disease of the newborn) Prevention by injecting antibodies against Rh factor in 4th month of pregnancy/72h after birth

END OF THE LECTURE

T CELLS
Originate In Bone Marrow And Migrate To The Thymus ( A Gland Above The Heart)

Develop The Ability To Identify Microbes

Millions Of Different T Cells, Each Recognizes One Particular Antigen No Invaders Can Escape Being Recognized By At Least Few T Cells

4 Kinds Of T cells: Inducer T Cells, Helper T Cells (Th), Cytotoxic T Cells (Tc) And Suppressor T Cells (Ts)

 Inducer T Cells : T cell maturation Not involved in the immediate response to infection Mediates the maturation of other T cells in the thymus Helper T Cells : Immunoregulation Commander of the immune response Detects infection and sounds the alarm Initiating both T cells and B cells responses Cytotoxic T Cells : Cytotoxicity Detects and kills infected body cells Recruited by helper T cells Suppressor T Cells : Immunosuppression Dampens the activity of T and B cells Scaling back the defense after the infection has been checked

MHC PROTEINS: -Glycoprotein Present On All Cells -Produced by Major Histocompatibility Gene Complex

E.g. Human Leukocyte Antigen (HLA) and H-2 (mice)

-Highly Polymorphic

MHC Proteins: Biochemial Fingerprints

MHC Protein On Cell Serve As Self Markerenabling The Individuals Immune System To Distinguish Its Cells From Foreign Cells This Property Is C/a Self-versus-non-self Recognition

CONDT..
Antigen-presenting Cells: Presents processed Microbial Antigen with the MHC Proteins Two Types of MHC Proteins:
(1) MHC I: Every Nucleated Cells
-Cytotoxic T Cells: Antigen With MHC I Proteins

(2) MHC II: Only on Macrophages, B Cells, and Subtype of T Cells C/a CD4+ T Cells.
-Helper T Cells: Antigen Presented With MHC II Protein

Antigens are presented on MHC proteins

CONDT..
CD8 Coreceptor: Present On Cytotoxic T Cells, Interact Only With MHC I Proteins Of Infected Cells These Cells Are Indicated As CD8+ CD4 Coreceptor: Present On Helper T Cells Interact Only With MHC II Proteins These Cells Are Indicated As CD4+

Key Cell surface proteins of the immune system

The Cell-Mediated Immune Response:

Antigen

Presentation with MHC proteins initiate helper T cells responses Cytotoxicity: Infected and cancer cells killing Secretion :cytokines or interleukins (25) Act by binding to the cell membrane receptors IL-1:Secreted by macrophage & activate T cells IL-2: Released by Th cells & activates CTLs IL-4 :Secreted by T cells and stimulates B cells

Step 1: When macrophages process the foreign antigens,they secrete IL-1

Step 2:Interleukin-1 stimulates cell division and proliferation of T cells

Step 3: Helper T cells then secrete Interleukin-2, which stimulates the proliferation of cytotoxic T cells

Step 4: Cytotoxic T cells recognize and destroy body cells infected with the virus can only destroy infected cells that display the foreign antigen together with their MHC proteins As infection subsides, suppressor T cells turn off the immune response
* They

Cytotoxic T cell (orange) destroying cancer cell (pink)

Acquired Immune Deficiency Syndrome

AIDS : Immune system gets attacked

Inactivates Helper T cells: immunoregulator

Recognizes CD4+ coreceptors

Cripples the immune system in at least 3 ways:

~ HIV-infected CD4+ T cells are destroyed

~These cells secrete factors that block other T cells from responding to the HIV antigen
~HIV block transcription of MHC gene

HIV (red) released from infected CD4+ T cells infecting other CD4+ T cell

CD4+ T cells are destroyed rapidly

The global AIDS epidemic

T-cell destruction: AIDS

Vulnerable : Common infections proves fatal

Max. AIDS victims dies of cancer

The fatality rate of AIDS is 100%

Not highly contagious Through body fluid (blood and semen)

Drugs (Price): AZT (Reverse transcriptase inh.) & protease inhibitor : viral assembly Vaccine : Splicing HIV surface protein gene into vaccinia virus (antigenic shifting)